tbuckley/cabot-search huggingface dataset:
Abstract 1431: Sprouty 2 expression attenuates proliferation in nras-driven acute myeloid leukemia cell lines
Authors: Michael Roberts, Sher Bahadur, Coltin Albitz, Jae Chung, Samantha Garcia, Cuong Nguyen, Sophia Kovatsis
Journal: Cancer Research (2023)

Abstract Oncogenic mutations in the NRAS gene are found in many cancers including a subset of acute myeloid leukemias (AML). Established AML cell lines exhibiting hyperactive signaling through the RAS-RAF-MEK-ERK pathway show constitutive ERK activation generating a transcriptome that mediates escape from programmed cell death and continuous proliferation. It has been established that exposure of many AML cell lines to phorbol esters such as phorbol-12-myristate-13-acetate (PMA) mediates cell cycle arrest, myeloid differentiation, and apoptosis. This effect seems counterintuitive given that PMA irreversibly activates protein kinase C (PKC), which enhances ERK activity leading to transcriptional upregulation of target genes controlled by ERK activated transcription factors, many of which promote proliferation. Here we define a set of PMA response genes in AML cell lines driven by oncogenic NRAS that encode negative regulators of RAS-RAF-MEK-ERK signaling, including SPRY2, RASA1, DUSP 5, and DUSP6. Additionally, we show that overexpression of SPRY2 alone attenuates proliferation by inhibiting ERK activation and altering the AML cell transcriptome through the activation of genes encoding members of the AP-1 transcription factor family, FOS, JUNB, and JUND, and the cyclin-CDK inhibitors CDKN1A and CDKN2B. We hypothesize that oncogenic NRAS signaling is overridden by PMA treatment through the activation of ERK target genes that ultimately inhibit the MAPK-ERK pathway, such as SPRY2. Finally, we show that SPRY 2 expression in AML patient samples represents a survival prognostic indicator where higher expression levels correlate with improved overall survival. Citation Format: Michael Roberts, Sher Bahadur, Coltin Albitz, Jae Chung, Samantha Garcia, Cuong Nguyen, Sophia Kovatsis. Sprouty 2 expression attenuates proliferation in nras-driven acute myeloid leukemia cell lines [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1431.
Abstract 189: Developing a patient-derived organoid biobank, suitable for large scale drug screenings
Authors: Lars-Eric Fielmich, Annemarie Buijs, Daniele Mori, Bas Viergever, Nihed Draoui, Anna Schepers, Mariana M. Costa e Silva, Mathijs Scholtus, Tokameh Mahmoudi, Tahlita Zuiverloon, Merel Derksen, Paul Gavine, Sylvia F. Boj, Richard Meijer, Onno Kranenburg, Janine Arts, Robert Vries
Journal: Cancer Research (2023)

Abstract Conventional models for preclinical drug screening offer poor predictive value for patient response, causing high attrition rates of new agents in the clinic. HUB’s proprietary Patient-Derived Organoid (PDO) Technology enables long-term expansion of primary patient material to generate ‘mini organs in a dish’ that can be used as patient avatars, thus bringing every “patient in the lab®”. We present the world’s first NMIBC PDO biobank comprising 50 PDO models from transurethral resection of bladder (TURB) biopsies collected at three hospitals. Clinical and pathological characterization of the PDOs confirmed the representation in the biobank of a range of tumor stages and differentiation grades, as well as patient treatment and follow-up. The genomic analyses of PDOs revealed mutations in known BC driver genes and genomic instability, a hallmark of cancer. Finally, transcriptomic analyses confirmed gene expression profiles familiar to BC and characterized gene fusions. Next, we successfully screened the biobank on a panel of two reference compounds for the treatment of bladder cancer and seven candidate drugs, indicating potential new leads for further development of some of the compounds. The work presented here shows the feasibility of building PDO biobanks representing a specific patient population, suitable for improving the drug development pipeline for the next generation of cancer drugs. Citation Format: Lars-Eric Fielmich, Annemarie Buijs, Daniele Mori, Bas Viergever, Nihed Draoui, Anna Schepers, Mariana M. Costa e Silva, Mathijs Scholtus, Tokameh Mahmoudi, Tahlita Zuiverloon, Merel Derksen, Paul Gavine, Sylvia F. Boj, Richard Meijer, Onno Kranenburg, Janine Arts, Robert Vries. Developing a patient-derived organoid biobank, suitable for large scale drug screenings [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 189.
Abstract 4937: Immunoproteasome inhibitors for the treatment of t(4;11)-driven ALL
Authors: Alexei F. Kisselev, Tyler W. Jenkins, Elise Fitzerald, Andrey V. Maksimenko, Peter Panizzi, Jennifer L. Fields, Steven N. Fiering, Amit K. Mitra
Journal: Cancer Research (2023)

Abstract The t(4;11)(q21;q23) chromosomal translocation that creates the MLL-AF4 fusion protein, confers a poor prognosis in infant acute lymphoblastic leukemia (ALL). This translocation also sensitizes cells to proteasome inhibitors bortezomib and carfilzomib, which are approved by the FDA for the treatment of multiple myeloma. Clinical activity of bortezomib in combination with standard chemotherapy has been documented in several clinical trials of ALL patients, and a case of a single-agent activity against relapsed leukemia driven by the MLL-AF4 translocation has been described. However, toxicities of bortezomib and carfilzomib may be unacceptable to pediatric patients. We found that the overwhelming majority of proteasomes in this subtype of ALL are lymphoid tissue specific immunoproteasomes. Cells with MLL-AF4 translocations were sensitive to pharmacologically relevant concentrations of specific immunoproteasome inhibitors ONX-0914 and M3258. Furthermore, both compounds dramatically delayed growth of orthotopic xenograft tumors in mice. Thus, immunoproteasomes are therapeutic targets in ALL and replacing bortezomib and carfilzomib with immunoproteasome inhibitors in ALL should reduce toxicities associated with inhibition of the proteasomes in non-lymphoid tissues. Citation Format: Alexei F. Kisselev, Tyler W. Jenkins, Elise Fitzerald, Andrey V. Maksimenko, Peter Panizzi, Jennifer L. Fields, Steven N. Fiering, Amit K. Mitra. Immunoproteasome inhibitors for the treatment of t(4;11)-driven ALL. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4937.
Asymmetric gene expression and cell-type-specific regulatory networks in the root of bread wheat revealed by single-cell multiomics analysis
Authors: Lihua Zhang, Chao He, Yuting Lai, Yating Wang, Lu Kang, Ankui Liu, Caixia Lan, Handong Su, Yuwen Gao, Zeqing Li, Fang Yang, Qiang Li, Hailiang Mao, Dijun Chen, Wei Chen, Kerstin Kaufmann, Wenhao Yan
Journal: Genome biology (2023)

Homoeologs are defined as homologous genes resulting from allopolyploidy. Bread wheat, Triticum aestivum, is an allohexaploid species with many homoeologs. Homoeolog expression bias, referring to the relative contribution of homoeologs to the transcriptome, is critical for determining the traits that influence wheat growth and development. Asymmetric transcription of homoeologs has been so far investigated in a tissue or organ-specific manner, which could be misleading due to a mixture of cell types.
Abstract 5902: The immune features of Helicobactor pylori-positive gastric cancer provides insights into immunotherapy
Authors: Keren Jia, Yang Chen, Xiaoyi Chong, Yilin Li, Jiajia Yuan, Yanyan Li, Xiaotian Zhang, Jian Li, Lin Shen
Journal: Cancer Research (2023)

Abstract Introduction: Helicobactoer pylori (H. pylori) is one of the most important risk factors of gastric cancer (GC). However, the effects of Helicobacter pylori on the immune microenvironment and its potential roles in tumor immunotherapy responses is still lacking. Methods: We included 61 patients, 46 of whom received anti-PD-1/PD-L1 based immunotherapy. Patients’ samples at baseline were collected and examined with multiplex immunothistochemistry. Four detecting panels including 16 kinds of antibodies were used to label CD8+ T cells, CD4+ T cells, B cells, macrophages, neutrophils, and their functional status. Immunotherapy-related overall survival (irOS) is the interval from the initiation of immunotherapy to death or the last following up. mmunotherapy-related progression-free survival (irPFS) is the interval from the initiation of immunotherapy to disease progression or the last following up. The Student’s t test is used to compared the average density of immune cells. The Chi-squared test was used to compare the objective response rate (ORR) between two groups. Results: H. pylori-positive rate was 29/61. In 46 patients received immunotherapy, 23 patients were infected with H. pylori. There was a increasing trend for the density of CD8+ T cells, B cells, and neutrophils in H. pylori-positive patients compared with negative group. We observed that the densities of total CD4+ T cells, CD4+PD-L1+, and CD4+CTLA-4+ T cells, were higher in H. pylori-positive group compared with negative group (522.58 vs. 268.77/mm^2, P=0.020, 118.94 vs. 265.98/mm^2, P=0.0091; 61.30 vs. 18.56/mm^2, P=0.035). In addition, STING positive macrophages (CD68+STING+ cells) were also enriched in H. pylori-positive group than negative group (138.45 vs. 44.15/mm^2, P=0.0012). Next, we found H. pylori-positive patients harbored higher ORR than negative group (47.62% vs. 17.39%, P=0.032). However, there were no significant difference of irPFS and irOS between positive and negative group (median irPFS: 5.97 vs. 6.83 months, hazard ratio: 1.02, P=0.96; median irOS: 12.83 vs. 10.97 months, hazard ratio: 0.855, P=0.59). Conclusions: We observed the enrichment of total CD4+ T cells, CD4+PD-L1+ T cells, CD4+CTLA-4+ T cells, and CD68+STING+ cells in H. pylori-positive patients, indicating the combination of anti-CTLA-4 or STING may enhance the efficacy of immunotherapy in H. pylori-positive GC. Citation Format: Keren Jia, Yang Chen, Xiaoyi Chong, Yilin Li, Jiajia Yuan, Yanyan Li, Xiaotian Zhang, Jian Li, Lin Shen. The immune features of Helicobactor pylori-positive gastric cancer provides insights into immunotherapy. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5902.
Abstract 561: Development of competing and non-competing fully human internalizing anti-Her2 monoclonal antibodies
Authors: Ginette Serrero, Binbin Yue, Jianping Dong, Chun Dong, Jun Hayashi
Journal: Cancer Research (2023)

Abstract The human epidermal growth factor receptor (HER) family of receptors has been implicated in several human cancers. Among them, HER2 is overexpressed in several cancers with or without gene amplification with prognostic and predictive implications. In 15-30% of breast cancers, HER2 overexpression and amplification are associated with shorter disease-free and overall survivals along with resistance to hormonal agents as well as increased risk of brain metastasis. Two types of HER2 targeting have been developed: anti-HER2 monoclonal antibodies and small molecule tyrosine kinase inhibitors. Trastuzumab is a humanized anti-HER2 monoclonal antibody that binds to domain IV of HER2 extracellular segment and blocks its signaling. It is the first therapeutic antibody targeting Her2 overexpression approved by the FDA. More recently, two antibody drug conjugates using trastuzumab have been approved: Ado-Trastuzumab-Emtansine (Kadcyla) consisting of trastuzumab conjugated to the drug mertansine DM1 and fam-trastuzumab-deruxtecan-nhki (Enhertu to deliver the topoisomerase inhibitor deruxtecan. We are reporting here the development of fully human internalizing anti-Her2 antibodies that compete or not with trastuzumab for binding to Her2. These antibodies have been developed by immunizing fully human (TC-Mab mouse) mice with recombinant Her2 protein. After production of hybridoma secreting fully human immunoglobulins, the screening process included inhibition of binding of trastuzumab to Her2 by enzyme linked immunoassay and by Octet epitope binning as well as internalization assay. Several internalizing antibodies able to compete or not with trastuzumab and with high affinity (Kd ranging from 10−9 M to 10−12 M) were selected. They were next investigated for their ability to deliver a cytotoxic payload in HER2 overexpressing cells breast cancer cells such as SKBR3, BT474 and AU565. Two antibodies: one competing with trastuzumab and the other one non-competing were further characterized. Data related to these antibodies’ biochemical characteristics as well as their ability to inhibit proliferation in vitro and in vivo in mouse xenografts studies will be presented here. In conclusion, the use of fully human mice in our laboratory provides a powerful and attractive approach to develop fully human monoclonal antibodies against cancer targets allowing to by-pass the need for humanization and affinity maturation of antibodies. Citation Format: Ginette Serrero, Binbin Yue, Jianping Dong, Chun Dong, Jun Hayashi. Development of competing and non-competing fully human internalizing anti-Her2 monoclonal antibodies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 561.
Abstract 5906: Gut microbiota signatures are associated with immunotherapy induced cognitive decline and neurotoxicity
Authors: Anik Banerjee, Christina Roland, Sarah Johnson, Nadim Ajami, Jennifer Wargo
Journal: Cancer Research (2023)

Abstract Studies have demonstrated promising outcomes of combined immune checkpoint blockade (CICB) modulating tumor cytotoxicity via targeting cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) and programmed cell death 1 (PD-1). The emergence of long-term patient management has been transformed among health care professionals as patient survival rates are increasing significantly. Despite promising advances, patient outcomes are heterogenic and are correlative to host intrinsic and extrinsic factors. Multiple reports have highlighted the negative effects of cancer treatments towards inducing cognitive impairment and neurotoxicity often referred to as “chemofog”. More recently, the gut microbiome has been increasingly recognized to regulate antitumor immunity and further distinct microbiome signatures can confer favorable outcomes in the context of CICB. Interestingly, specific microbes within the gut microbiome have been shown to regulate social behavior and cognition via the bidirectional communication along the gut-brain axis though changes in microbiota-derived metabolites and vagal afferent fibers. Insights into mechanisms of immunotherapy induced cognitive decline are warranted. Thus, we hypothesize CICB exacerbates cognitive impairment and neurotoxicity via the detrimental alterations to the gut microbiome. To address this, we profiled the gut microbiome, through 16S rRNA gene and metagenomic sequencing of fecal samples from patients (n=146) with advanced melanoma treated with CICB stratified based on severity of cognitive dissonance. Beta-diversity, incorporating weighted UniFrac distances by principal coordinate analysis (PCoA), revealed a cluster of samples from patients with cognitive impairment as compared to samples from those with minimal to absent cognitive decline. Further, taxonomical analysis showed significant alterations in relative abundances of microbial candidates (e.g., L. intestinalis, A. muciniphila, F. prausnitizii, and R. hominis). These results suggests that CICB patients with cognitive impairments and neurotoxicity have altered microbiome signatures which may potentially exacerbate downstream neuroinflammatory signaling. Further studies investigating specific host-microbe pathways and profiling microbiota-derived metabolites which are implicated in these detrimental effects are essential for biomarker discovery and mechanistic insight. Citation Format: Anik Banerjee, Christina Roland, Sarah Johnson, Nadim Ajami, Jennifer Wargo. Gut microbiota signatures are associated with immunotherapy induced cognitive decline and neurotoxicity. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5906.
STING Protein‐Based In Situ Vaccine Synergizes CD4<sup>+</sup> T, CD8<sup>+</sup> T, and NK Cells for Tumor Eradication
Authors: Yanpu He, Celestine Hong, Shengnan Huang, Justin A. Kaskow, Gil Covarrubias, Ivan S. Pires, James C. Sacane, Paula T. Hammond, Angela M. Belcher
Journal: Advanced Healthcare Materials (2023)

Stimulator of interferon genes (STING) signaling is a promising target in cancer immunotherapy, with many ongoing clinical studies in combination with immune checkpoint blockade (ICB). Existing STING-based therapies largely focus on activating CD8
Abstract 4653: Spatial architecture of tumor-infiltrating macrophagesorchestrates tumor immunity and therapeutic response
Authors: Yuanyuan Zhang, Fuduan Peng, Guangsheng Pei, Yunhe Liu, Guangchun Han, Linghua Wang
Journal: Cancer Research (2023)

Abstract Tumor-infiltrating macrophages, a major cellular component in the tumor microenvironment (TME), have been proven to be linked with tumor progression and immunotherapy resistance. Tremendous heterogeneity has been revealed for tumor-associated macrophages (TAMs) in different cancer types, however, how these TAM subtypes are localized and interact with tissue ecosystems remains poorly understood. Here, we perform an integrative analysis of TAMs, malignant and non-malignant cells from 10 cancer types, based on single-cell RNA-seq and spatial transcriptomic data. By interrogating the spatial distributions of different TAM subtypes in situ, we reveal spatially restricted developmental, regulation, and functional heterogeneity of TAMs in TME. Different cancer types show distinct TAM subtype enrichments with specific interface architectures, which is potentially shaped by the cellular compositions and spatial niches of tumor cells. Furthermore, the compartmentalized TAM subpopulations can reflect the spatial architecture of surrounding stromal and immune cells, and thus orchestrate tumor immunity and therapeutic response. Our study demonstrates the cellular and molecular underpinnings of TAM heterogeneity and stochastic regulations of TAMs for TME architecture, tumor progression and immunotherapy responses, which will assist in the identification of possible therapeutic targets. Citation Format: Yuanyuan Zhang, Fuduan Peng, Guangsheng Pei, Yunhe Liu, Guangchun Han, Linghua Wang. Spatial architecture of tumor-infiltrating macrophagesorchestrates tumor immunity and therapeutic response. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4653.
Abstract 5662: Early unwanted immunogenicity assessment of immuno oncology drugs
Authors: Sofie Pattyn, Martijn Vlaming, Alanah Pieters, Jana Schockaert
Journal: Cancer Research (2023)

Abstract Bispecifics targeting multiple antigens or epitopes have been showing great promise for treatment of cancer. However, managing unwanted immunogenicity has become a challenge in the development cycle of these promising therapeutics as there is a trend towards higher unwanted immune responses compared with classical monoclonal antibodies. In vitro assays using human primary immune cells can be used to assess the risk of induction of a cytokine release storm or induction of unwanted immunogenicity. For the latter, T cell activation and proliferation assays can be used to assess and predict an unwanted immune response and avoid induction of anti-drug antibodies later on. In order to achieve reliable and consistent results, high quality primary immune cells should be used in combination with sensitive fit-for-purpose in vitro assays. Citation Format: Sofie Pattyn, Martijn Vlaming, Alanah Pieters, Jana Schockaert. Early unwanted immunogenicity assessment of immuno oncology drugs. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5662.
Abstract 4847: Investigating the transcriptional regulation by estrogen-related receptor alpha (ERRα) under different metabolic conditions
Authors: Brittney A. Hua, Chien-yu Chen, Yang Li, Lina He, Bangyan Stiles, Ielyzaveta Slarve
Journal: Cancer Research (2023)

Abstract Estrogen-related receptors (ERRs) are orphan nuclear receptors identified based on their high sequence similarity to estrogen receptors (ERs), but ERRs do not have a known endogenous ligand. ERRs play a primary role in regulating the transcription of genes involved in mitochondrial and lipid metabolism and are abundantly expressed across tissues. Because of ERR’s role in metabolism, it is suggested that they may also play a role in tumor metabolism, where dysfunction in lipid metabolism promotes tumor cell growth. The ERR subfamily is comprised of three isoforms: ERRα, ERRβ, and ERRγ. Studies targeting the ERR isoforms found that the absence of ERRα presents obesity and insulin resistance with an increase in bone mass, deletion of ERRβ causes placental abnormalities and embryonic lethality, and deletion of ERRγ leads to mitochondrial dysfunction. Together, these studies strongly suggest that ERRs, particularly ERR α and γ, function primarily as metabolic regulators, with ERRα being the predominant isoform expressed in the liver. In addition, the mechanisms leading to lipid accumulation vary under different feeding conditions. Previous studies from our lab showed that PTEN and PI3K/AKT signaling regulates ERRa expression and its function. Furthermore, we demonstrated that inhibiting ERRα blocks liver steatosis and steatohepatitis developed in a mouse model where loss of tumor suppressor PTEN drives both steatosis and cancer development. In addition, we found that ERR-PA, a small molecule inhibitor for ERR, attenuated cancer cell growth and proliferation in both mouse hepatocytes and human cancer cell lines. Here, we report transcriptome network regulated by ERRα under different metabolic conditions and further explored its regulation by the PI3K/AKT pathway. A better understanding of the role ERRα plays in physiology will allow further development of ERR-PA as a potential therapy for liver steatohepatitis, which progresses to end stage cirrhosis and ultimately liver cancer. Citation Format: Brittney A. Hua, Chien-yu Chen, Yang Li, Lina He, Bangyan Stiles, Ielyzaveta Slarve. Investigating the transcriptional regulation by estrogen-related receptor alpha (ERRα) under different metabolic conditions. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4847.